Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis Journal Article

   


Authors: Ghashghaei, M.; Liu, Y.; Ettles, J.; Bombaci, G.; Ramkumar, N.; Liu, Z.; Escano, L.; Miko, S. S.; Kim, Y.; Waldron, J. A.; Do, K.; MacPherson, K.; Yuen, K. A.; Taibi, T.; Yue, M.; Arsalan, A.; Jin, Z.; Edin, G.; Karsan, A.; Morin, G. B.; Kuchenbauer, F.; Perna, F.; Bushell, M.; Vu, L. P.
Article Title: Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis
Abstract: Here the authors uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in leukemia. The work pointed to the potential of targeting the posttranscriptional circuitry via CNOT3 as a therapeutic vulnerability in acute myeloid leukemia. © The Author(s) 2024.; Protein synthesis is frequently deregulated during tumorigenesis. However, the precise contexts of selective translational control and the regulators of such mechanisms in cancer is poorly understood. Here, we uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in myeloid leukemia. Elevated CNOT3 expression correlates with unfavorable outcomes in patients with acute myeloid leukemia (AML). CNOT3 depletion induces differentiation and apoptosis and delayed leukemogenesis. Transcriptomic and proteomic profiling uncovers c-MYC as a critical downstream target which is translationally regulated by CNOT3. Global analysis of mRNA features demonstrates that CNOT3 selectively influences expression of target genes in a codon usage dependent manner. Furthermore, CNOT3 associates with the protein network largely consisting of ribosomal proteins and translation elongation factors in leukemia cells. Overall, our work elicits the direct requirement for translation efficiency in tumorigenesis and propose targeting the post-transcriptional circuitry via CNOT3 as a therapeutic vulnerability in AML. © The Author(s) 2024.
Keywords: genetics; leukemia, myeloid, acute; metabolism; protein; transcription factor; cell differentiation; proteomics; carcinogenesis; transcription factors; acute myeloid leukemia; detection method; vulnerability; chemokine receptor ccr4; cancer; humans; human; receptors, ccr4; ccr4 protein, human; cnot3 protein, human
Journal Title: Nature Communications
Volume: 15
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2024-03-15
Start Page: 2340
Language: English
DOI: 10.1038/s41467-024-46665-2
PUBMED: 38491013
PROVIDER: scopus
PMCID: PMC10943099
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85187890433&doi=10.1038%2fs41467-024-46665-2&partnerID=40&md5=999810a778ba2b9374e1b4e22c9407e9
Notes: Article -- Erratum issued, see DOI: 10.1038/s41467-024-53071-1 -- Source: Scopus
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